The present invention relates to a series of new 1.5-benzothiazepine derivatives which are useful in the treatment and prophylaxis of cardiovascular disorders. The invention also provides methods and compositions using these compounds as well as processes for their preparation.
It is now well established that the influx of calcium ions into certain cells in the mammalian body. including the vascular smooth muscle cells and miocardial cells, participates in the activity of such cells and that the administration of calcium channel blockers (also known as calcium antagonists), which inhibit such influx, would suppress myocardial contractile force and rate and cause Vasodilation. The calcium channel blockers are, therefore, useful in the treatment of a variety of diseases and disorders of the heart and vascular system, such as angina pectoris, myocardial infarction, arrhythmia, hypertension, cerebrovascular spasm and other ischemic disease.
A number of compounds having calcium channel blocking activity is known, for example certain dihydropyridine derivatives, such as nifedipine and nicardipine, and other compounds such as verapamil, diltiazem and flunarizine. Of these, nifedipine and nicardipine are widely used, but are structurally unrelated to the compounds of the present invention. Verapamil and flunarizine are also structurally unrelated to the compounds of the present invention. Diltiazem, whose systematic name is (2, 3S)-cis-3-acetoxy-2,3-dihydro-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl) -1,5-benzothiazepin-4(5H)-one is structurally related to the compounds of the present invention and is widely used for the amelioration of angina pectoris and for the therapy of essential hypertension; it is disclosed in Japanese Patent Publication Kokoku (i.e. published for opposition) No. 43785/1971 which also discloses other related compounds including some having a halo9en substituent on the benzene ring forming part of the benzothiazepine system. Subsequently, derivatives of diltiazem having a substituent for example a chlorine atom, at the 8-position, for example cis-3-acetoxy-8-chloro-2,3-dihydro-5-(2-dimethylaminoethyl)-2-(4-methoxyph enyl)-1,5-benzothiazepin-4(5E,uns/H/ )-one (8-chloro-diltiazem) were U.S. Pat. Specification No. 4 590 188 discloses a number of other derivatives including, for example, cis-3-acetoxy-8-methoxy-2,3-dihydro-5-(2-dimethylaminoethyl)-2-(4-methoxyp henyl)-1,5-benzotbiazepin-4(5E,uns/H/ )-one (8-methoxy-diltiazem), cis-3-acetoxy-8-benzyloxy- 2,3-dihydro-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)-1,5-benzothiazepi n-4(5H)-one (8-benzyloxy-diltiazem), and so on. These derivatives were said to have a stronger action and/or persistency than diltiazem.
We have now discovered a series of new 3-acyloxy-8-substituted-2,3-dihydro-5-(2-dimethylaminoethyl)-2-(optionally substituted phenyl)-5-benzothiazepin-4(5H)-one derivatives which have a potent calcium channel blocking activity and which have a better duration of activity than do the compounds of the prior art. The compounds of the present invention differ from the prior art benzothiazepine compounds in the nature of the substituent at the 8-position of the 1,5-benzothiazepin group.